核苷酸转运体表达与吉西他滨治疗胰腺癌患者临床疗效相关性的研究进展

目的 探讨核苷酸转运体表达与吉西他滨抗胰腺癌临床疗效相关性的研究进展。方法 通过查阅国内外文献,对相关研究归纳、总结进行综述。结果 吉西他滨是胰腺癌化疗的一线药物,较大个体化差异和有效率偏低是目前临床应用的挑战,核苷酸转运体是吉西他滨摄取入细胞的内吞转运体,它的蛋白或mRNA表达可能与接受吉西他滨治疗胰腺癌患者的临床疗效和不良反应相关,但尚未达成共识。结论 核苷酸转运体表达与吉西他滨抗胰腺癌临床疗效的相关性还需要进一步研究,为吉西他滨在胰腺癌中实现临床个体化治疗提供参考依据。     

基于常见遗传变异和传统风险因素的中国南方汉族人群结直肠癌风险预测模型研究

目的 基于结直肠癌全基因组关联研究(GWAS)发现的易感位点,联合传统风险因素建立中国南方汉族人群结直肠癌风险预测模型。方法 对1 066例结直肠癌患者和3 880例健康对照的21个GWAS候选位点进行基因分型,分析其与结直肠癌易感性之间的关联。通过遗传风险评分(GRS)和加权遗传风险评分(wGRS)计算显著候选位点的联合效应。以不同方式组合遗传风险评分和传统风险因素,构建结直肠癌风险预测模型,并绘制受试者工作特征曲线评价模型优劣性。结果 7个候选位点与结直肠癌易感性显著相关。随着风险评分的升高,人群患结直肠癌的风险也随之升高(GRS:P=0.002 6,wGRS:P<0.000 1),相比于四分位分组中最低一组,GRS和wGRS最高的一组OR值分别为1.33(95%CI:1.12~1.58,P=0.001 0)和1.76(95%CI:1.45~2.14,P<0.000 1)。联合传统风险因素和wGRS的模型为最优模型,其曲线下面积为0.593(95%CI:0.573~0.613)。结论 结直肠癌易感位点间存在显著的联合作用。相比于传统风险因素模型,传统风险因素结合加权遗传风险评分模型能更好预测结直肠癌的患病风险。     

Choosing blindly but wisely: differentially private solicitation of DNA datasets for disease marker discovery

Objective To propose a new approach to privacy preserving data selection, which helps the data users access human genomic datasets efficiently without undermining patients’ privacy.Methods Our idea is to let each data owner publish a set of differentially-private pilot data, on which a data user can test-run arbitrary association-test algorithms, including those not known to the data owner a priori. We developed a suite of new techniques, including a pilot-data generation approach that leverages the linkage disequilibrium in the human genome to preserve both the utility of the data and the privacy of the patients, and a utility evaluation method that helps the user assess the value of the real data from its pilot version with high confidence.Results We evaluated our approach on real human genomic data using four popular association tests. Our study shows that the proposed approach can help data users make the right choices in most cases.Conclusions Even though the pilot data cannot be directly used for scientific discovery, it provides a useful indication of which datasets are more likely to be useful to data users, who can therefore approach the appropriate data owners to gain access to the data.     

微粒体环氧化物水解酶基因多态性与膀胱移行细胞癌发生的关系

目的 探讨微粒体环氧化物水解酶(mEH)基因型与膀胱移行细胞癌(BTCC)的相关性.方法 应用聚合酶链反应—限制性片段长度多态性分析方法检测BTCC患者(BTCC组,216例)和健康人群(对照组,300例)mEH基因型频率的分布.设计流行病学调查问卷进行面访调查.结果 BTCC组野生型、杂合型和变异型mEH第3外显子(mEH-exon3)分别占60.6％、27.3％和12.0％,对照组分别占46.3％、39.0％和14.7％ (P＜0.05);杂合型mEH-exon3为BTCC发生的保护性因素(OR=0.56,95％ CI=0.41-0.82).BTCC组野生型、杂合型和变异型mEH第4外显子(mEH-exon4)分别占85.6％、13.4％和0.9％,对照组分别占82.3％、15.0％和2.7％(P＞0.05).吸烟的mEH-exon3野生型人群的BTCC风险高于不吸烟者(P＜0.05).结论 mEH-exon3非野生型可能是BTCC发生、发展中的保护性因素之一;吸烟为BTCC发生的重要危险因素.而mEH-exon4基因多态性和BTCC的发生无明显相关性.     

A preliminary identification of PIN1 SNP linkage in patients with coronary heart disease from Handan,China

Our aim was to perform an initial assessment of the polymorphic patterns of the PIN1 gene in patients with coronary heart disease (CHD). The PIN1-encoded protein (Pin1) suppresses eNOS-NO signaling and may impair cardiovascular function. Blood collection, DNA extraction, PCR amplification and gene sequencing were performed for thirty CHD participants living in central China, focusing on nine single nucleotide polymorphisms (SNPs). Their genetic linkages were revealed and their allele frequencies were compared with SNP data from the NCBI. Three major linkage patterns were identified: [1.rs2287839-5.rs2233682], [3.rs2233679-4.rs1077220–8.rs2287838] and [6.rs889162-7.rs2010457], suggesting correlated involvement in CHD and possible simultaneous genetic origin in ancient times. The frequencies of six SNPs are consistent with the NCBI data, while the frequencies of three SNPs (2.rs2233678, 4.rs1077220 and 9.rs4804461) are not consistent with the NCBI. Especially, the 3.rs2233679–4.rs1077220 linkage is different from other populations worldwide and may be an interesting genetic characteristic of Chinese CHD patients. Predictably, 1.rs2287839, 2.rs2233678, 3.rs2233679 and 5.rs2233682 may be strongly associated with CHD risk, although this requires future verification. The PIN1 SNP linkages lay a new genetic foundation for discovering novel molecular mechanisms of CHD and for exploring PIN1-based targeted treatment of CHD with nitric oxide regulatory therapies in clinical practice.     

白细胞介素-23受体基因多态性与炎症性肠病关系的初步研究

目的 初步探讨白细胞介素-23受体(IL23R)基因中两个单链核苷酸多态性(SNP)位点(rs11209026和rs11805303)的遗传多态性和炎症性肠病(IBD)的发病易感性之间的关系.方法 采用聚合酶链反应(PCR)直接测序法检测50名健康人和81例IBD患者(其中克罗恩病41例,溃疡性结肠炎40例)的两个SNP位点基因多态性.结果 rs11209026位点基因型频率和等位基因频率在克罗恩病患者分别为7.3%和3.7%,在溃疡性结肠炎患者分别为15.0%和7.5%,在对照组分别为14.0%和7.0%,三组间差异均无统计学意义(P值均＞0.05).rs11805303位点的基因型频率和等位基因频率在克罗恩病患者分别为22.0%和52.4%,在溃疡性结肠炎患者分别为15.0%和41.2%,在对照组分别为34.0%和59.0%,三组间基因型频率比较差异均无统计学意义(P值均＞0.05),而等位基因频率在溃疡性结肠炎患者和对照组间差异有统计学意义(P=0.018).rs11805303位点基因多态性与溃疡性结肠炎患者的发病年龄、性别、疾病的活动性及发病部位均无关(P值均＞0.05).结论 IL23R两个SNP位点基因多态性与克罗恩病无相关性.rs11805303位点的多态性可能为溃疡性结肠炎患者的一个遗传标志,但与该病病变特点无显著相关.     

Association of <Emphasis Type="Italic">SLC22A4/5</Emphasis> Polymorphisms with Steroid Responsiveness of Inflammatory Bowel Disease in Japan

Purpose We investigated the association between steroid responsiveness and single nucleotide polymorphisms of SLC22A4/A5 located within inflammatory bowel disease 5 locus. Our goal is personalized steroid therapy adjusted to match individual variations in drug responsiveness in each inflammatory bowel disease patient. Methods Unrelated Japanese cohorts of 94 patients with Crohn’s, 94 patients with ulcerative colitis, and 257 healthy control subjects were consecutively enrolled in this study. Genotyping and haplotype analysis focusing on steroid responsiveness was performed by using 15 single nucleotide polymorphisms. Results The G allele of −368T > G in SLC22A5, in which strong linkage disequilibrium was observed and the limited diversity of three haplotypes was estimated, was significantly associated with steroid resistance in Japanese patients with Crohn’s disease (P = 0.016). Haplotype analysis between −446C > T and −368T > G in the SLC22A5 promoter region showed that the CG allele appeared to be a risk haplotype for steroid resistance (CG: odds ratio, 4.13; 95 percent confidence interval, 1.41–12.1; P = 0.016). Conclusions This extensive linkage disequilibrium may form a general risk haplotype for steroid resistance in Crohn’s disease in Japanese. Further analyses of the pharmacogenomics of steroid responsiveness are warranted to achieve the goal of individualized steroid therapy against inflammatory bowel disease. Supported by a grant-in-aid from the Ministry of Health, Labour and Welfare (K.I.), Japan. Address of correspondence: Yoshiaki Arimura, M.D., First Department of Internal Medicine, Sapporo Medical University, S-1, W-16, Chuo-ku, Sapporo, 060-8543, Japan. E-mail: arimura@sapmed.ac.jp     

Linkage of four polymorphisms on the αIIb gene

The subunits of the platelet integrin α_IIbβ₃ are encoded by two genes located on chromosome 17. Two pathologies are associated with structural modifications of this complex: Glanzmann's thrombasthenia and alloimmune thrombocytopenia. The former is a hereditary bleeding disorder, the latter is due to an immune response linked to the presence of specific epitopes defined by single amino acid substitutions called human platelet alloantigen (HPA) systems. Analysing the α_IIb gene from 112 independent chromosomes, we have defined two new silent polymorphisms in complete linkage disequilibrium. They are reciprocally linked to HPA-3 and a previously reported 9 pb deletion in intron 21. Linkage of these four DNA markers spanning a 5 kb fragment of genomic DNA provides a new tool for analysing α_IIb gene pathology and evolution.     

早发冠心病患者脂蛋白脂酶基因多态性与血脂关系研究

目的:探讨早发冠心病(CHD)患者脂蛋白脂酶(LPL)基因多态性特征及其与血脂关系。方法:收集106例早发CHD患者(早发CHD组)血脂参数等资料,应用聚合酶链反应-限制性片段长度多态性方法,分析LPL的P、H基因型及其等位基因频率分布(HindⅢ和PVUⅡ酶切),并与81例非CHD者(对照组)进行比较。结果:早发CHD组血清胆固醇(TC)、甘油三酯(TG)和低密度脂蛋白胆固醇(LDL-C)水平较对照组明显升高(P<0.05),高密度脂蛋白胆固醇(HDL-C)水平较对照组降低(P<0.05)。早发CHD组P+,H+等位基因频率高于对照组(P<0.05)。H+H+基因型TC、TG明显高于H+H-基因型,HDL-D低于H+H-基因型;P+P+基因型TG明显高于P-P-基因型,HDL-C低于P-P-基因型(均P<0.05)。结论:早发CHD患者血清TC、TG和LDL-C高于对照组,HDL-C低于对照组;P+,H+等位基因频率高于对照组。H+H+和P+P+基因型影响血脂水平。     

冠心病病变范围与载脂蛋白E基因多态性及血脂分布的关系

目的 :探讨冠心病 (CHD)病变范围与载脂蛋白E(apoE)基因多态性及血脂分布的关系。 方法 :用酚氯仿抽提核酸法从凝血块中分离DNA ,用多聚酶链式反应 限制性片段长度多态性 (PCR RFLP)方法对新疆乌鲁木齐地区维、汉两民族人群中 10 2例CHD患者和 5 1例对照组人群进行apoE基因多态性 (由ε2、ε3和ε4决定的E2 / 2、E3/ 3、E4 / 4、E4 / 2、E4 / 3和E3/ 2 )HhaI酶切研究。结果 :①CHD组apoE之ε2 ,ε3和ε4等位基因频率分别为 0 .0 735± 0 .2 15 7,0 .774 5± 0 .3117和 0 .15 2 0± 0 .2 4 16 ,1支病变组apoE之ε2 ,ε3和ε4等位基因频率分别为 0 .10 6 1± 0 .2 4 2 3,0 .75 76± 0 .35 6 2和 0 .136 4± 0 .2 2 6 1,2支病变组apoE之ε2 ,ε3和ε4等位基因频率分别为 0 .0 5 5 6± 0 .1992 ,0 .80 5 6± 0 .2 995和 0 .1389± 0 .2 5 6 7,3支病变组apoE之ε2 ,ε3和ε4等位基因频率分别为 0 .0 6 0 6± 0 .2 0 76 ,0 .75 76± 0 .2 82 9和 0 .1818± 0 .2 4 4 3,与正常对照组 (0 .196 1± 0 .30 13,0 .6 6 6 7±0 .36 97和 0 .1373± 0 .2 2 5 4 )比较 ,ε2明显减低 (P <0 .0 5 ) ,病变范围越大 ,ε2越低 ,但病变范围大小之间统计学无差异 ,ε3和ε4随着病变范围增大逐渐升高但统计学无显著差别 (P >0